Neladalkib Proves Effective in TKI-Pretreated, Advanced ALK+ NSCLC

Neladalkib (NVL-655), an investigational ALK-selective inhibitor, generated responses in TKI-pretreated patients with advanced ALK-positive non–small cell lung cancer (NSCLC), according to data from the phase 1/2 ALKOVE-1 trial (NCT05384626).1

Among 253 evaluable TKI-pretreated patients, the overall response rate (ORR) per blinded independent central review (BICR) was 31% (95% CI, 26%-37%). At a median follow-up of 11.3 months, the median duration of response (DOR) was not reached (NR). A total of 64% (95% CI, 51%-75%) of patients had responses lasting at least 12 months, and 53% (95% CI, 34%-68%) of patients had responses lasting at least 18 months.

In the subset of patients who had received a prior TKI but were naive to lorlatinib (Lorbrena; n = 63), the ORR by BICR was 46% (95% CI, 33%-59%). In total, 80% (95% CI, 58%-91%) of patients had responses lasting at least 12 months, and 60% (95% CI, 19%-85%) of patients had responses lasting at least 18 months. The median DOR was NR.

“In treating [patients with] ALK-positive lung cancer, our goal is not only to help patients live longer, but also to help them live well with their disease,” Alice T. Shaw, MD, PhD, a thoracic oncologist at Dana-Farber Cancer Institute in Boston, Massachusetts, as well as an ALKOVE-1 trial investigator, stated in a news release. “These encouraging topline data suggest that neladalkib may represent a new and differentiated treatment option for ALK-positive lung cancer, offering durable clinical benefit [and] potentially reducing the risk of [adverse] effects [AEs] that can affect quality of life.”

Nuvalent, the developer of neladalkib, plans to discuss the data in the TKI-pretreated, ALK-positive NSCLC population with the FDA during a pre–new drug application meeting. Additionally, more detailed trial findings are expected to be presented at an upcoming medical conference.

“Today’s announcement adds to the growing body of research that is transforming potential outcomes for ALK-positive lung cancer and offering new hope to patients,” Kirk Smith, a patient and president of the Board of ALK Positive Inc., added in the news release. “We encourage the continued innovation and development of new therapeutic options for patients, with the hope that one day, advanced ALK-positive NSCLC could be managed as a chronic condition more often than as a life-threatening disease.”

The agent was generally well tolerated and had a safety profile that was consistent with that of its ALK-selective, TRK-sparing design, according to the news release. As of the data cutoff date, among patients with ALK-positive NSCLC who received neladalkib at the recommended phase 2 dose (RP2D), the median duration of exposure was 6.0 months (range, 0.1-28.4). In total, 17% of patients required dose reductions due to treatment-emergent AEs (TEAEs), and 5% of patients discontinued the agent due to TEAEs.

“We are deeply grateful to the patients, caregivers and investigators who have made this milestone possible for our neladalkib program,” James Porter, PhD, chief executive officer at Nuvalent, said in the news release. “I continue to be inspired by the unwavering dedication of the Nuvalent team to making a difference for patients and humbled by the courage and conviction of the over 1000 patients [who] have already chosen to receive neladalkib through either our ALKOVE-1 trial or our global Expanded Access Program. Our focus remains on delivering our precisely targeted therapies to patients as quickly as possible, and we look forward to discussing these pivotal data with the FDA and aligning on a potential registration path for neladalkib in TKI pre-treated patients with advanced ALK-positive NSCLC.”

What is the design of the ALKOVE-1 trial?

This first-in-human trial is investigating neladalkib in patients with advanced ALK-positive solid tumors, including NSCLC. The phase 1 dose-escalation portion of the trial identified the RP2D of the agent as 150 mg once daily. The global, single-arm, multicohort, open-label phase 2 portion, which has registrational intent, is examining the agent at the RP2D in patients with TKI-pretreated, advanced ALK-positive NSCLC. Additionally, global enrollment in the trial is ongoing for adult and adolescent patients with ALK-positive solid tumors other than NSCLC, as well as for adolescent patients with ALK-positive NSCLC.

To create the pivotal dataset for the TKI-pretreated ALK-positive NSCLC population, investigators pooled data across the phase 1 and phase 2 portions. The primary end point was ORR per BICR. Key secondary end points were DOR, intracranial ORR (IC-ORR), and safety.

What additional efficacy data were seen among patients with NSCLC in ALKOVE-1 who had received any prior ALK TKI with or without chemotherapy?

At a data cutoff date of August 29, 2025, 781 patients with ALK-positive solid tumors had received neladalkib at any starting dose across the phase 1 and phase 2 portions. Among those patients, 656 with advanced ALK-positive NSCLC received the agent at the RP2D.

The pivotal TKI-pretreated NSCLC dataset was composed of outcomes from 253 patients who received neladalkib at the RP2D by September 20, 2024. Notably, the duration of follow-up was at least 6 months for most responders. Patients in this cohort had received a median of 3 prior lines of therapy (range, 1-11), and 51% had been treated with prior chemotherapy. In total, 78% of patients had received at least 2 prior ALK TKIs with or without prior chemotherapy, of whom 91% had been treated with prior lorlatinib. Additionally, 19% of patients had a secondary ALK G1202R resistance mutation, and 17% of patients had a compound ALK resistance mutation. At baseline, 40% of patients had active central nervous system (CNS) disease per BICR.

Among patients with ALK G1202R mutations (n = 47), the ORR was 68% (95% CI, 53%-81%). Eighty percent (95% CI, 61%-91%) of patients had responses lasting at least 12 months, and 70% (95% CI, 42%-86%) of patients had responses lasting at least 18 months.

Among patients with measurable CNS lesions (n = 92), the IC-ORR was 32% (95% CI, 22%-42%), which included an IC complete response (IC-CR) rate of 13%. A total of 71% (95% CI, 48%-85%) of patients experienced responses lasting at least 12 months, and 71% (95% CI, 48%-85%) of patients had responses lasting at least 18 months.

What additional efficacy data were seen in ALKOVE-1 among TKI-pretreated patients with NSCLC who had not received prior lorlatinib?

In the lorlatinib-naive subset of patients, 25% had received prior chemotherapy. All patients in this subset had received at least 1 prior second-generation ALK TKI with or without prior chemotherapy; 70% of these patients had received prior alectinib alone. Notably, no patients received crizotinib as their only ALK TKI. Nineteen percent of patients in this subset had a secondary ALK G1202R mutation. At baseline, 40% of patients had active CNS disease per BICR.

Among patients in this cohort with ALK G1202R mutations (n = 12), the ORR was 83% (95% CI, 10%-12%). The rates of patients achieving responses that lasted at least 12 months and at least 18 months were both 77% (95% CI, 34%-94%).

Among patients with measurable CNS lesions (n = 24), the IC-ORR was 63% (95% CI, 41%-81%), including an IC-CR rate of 21%. The rates of patients achieving responses that lasted at least 12 months and at least 18 months were both 92% (95% CI, 57%-99%).

How has neladalkib performed in ALKOVE-1 in TKI-naive patients with advanced ALK-positive NSCLC?

Furthermore, preliminary data have been reported from the phase 2 ALKOVE-1 exploratory cohort of neladalkib in TKI-naive patients with advanced ALK-positive NSCLC and measurable disease per BICR who received neladalkib at the RP2D and could have received a maximum of 1 prior line of therapy (n = 44). At a data cutoff date of August 29, 2025, the preliminary ORR was 86%, and the CR rate was 9%. The DORs ranged from 1.7+ months to 14.8+ months. The rates of patients achieving responses that lasted at least 6 months and at least 12 months were both 91% (95% CI, 70%-98%). Progression events were only reported in 2 responders.

Among patients in this cohort with measurable IC lesions (n = 9), the IC-ORR was 78%, and the IC-CR rate was 44%. The IC-DORs ranged from 3.1+ months to 7.0+ months, and no responders experienced CNS progression.

What additional information is known about the safety profile of neladalkib?

In the population of patients with advanced ALK-positive NSCLC who received the agent at the RP2D, the most frequently reported TEAEs were increased alanine aminotransferase levels (47%), increased aspartate aminotransferase levels (44%), constipation (28%), dysgeusia (23%), peripheral edema (18%), cough (16%), and nausea (16%). The elevated transaminase levels were typically asymptomatic lab abnormalities that were low grade, transient, and reversible with dose reductions or interruptions.

What are the next steps for evaluating neladalkib?

Global enrollment of TKI-naive patients to the randomized phase 3 ALKAZAR trial (NCT06765109) is ongoing. This trial is investigating neladalkib vs alectinib (Alecensa) in patients with TKI-naive, advanced ALK-positive NSCLC.2 Notably, the trial protocol includes enhanced monitoring for elevated transaminase levels, as well as prompt dose interventions to mitigate this AE.1

References

1. Nuvalent announces positive topline pivotal data from ALKOVE-1 clinical trial of neladalkib for TKI pre-treated patients with advanced ALK-positive NSCLC. News release. Nuvalent, Inc. November 17, 2025. Accessed November 17, 2025. https://investors.nuvalent.com/2025-11-17-Nuvalent-Announces-Positive-Topline-Pivotal-Data-from-ALKOVE-1-Clinical-Trial-of-Neladalkib-for-TKI-Pre-treated-Patients-with-Advanced-ALK-positive-NSCLC
2. Neladalkib (NVL-655) for TKI-naive patients with advanced ALK-positive NSCLC (ALKAZAR). ClinicalTrials.gov. Updated November 4, 2025. Accessed November 17, 2025. https://clinicaltrials.gov/study/NCT06765109